Classifications

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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/62—Oxygen or sulfur atoms
  • C07D213/63—One oxygen atom
  • C07D213/64—One oxygen atom attached in position 2 or 6
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/72—Nitrogen atoms
  • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
  • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
  • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
  • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D237/14—Oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/52—Two oxygen atoms
  • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
  • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
  • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
  • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D241/18—Oxygen or sulfur atoms

Definitions

• the present invention provides non-nucleoside compounds and certain derivatives thereof which are inhibitors of RNA-dependent RNA viral polymerase. These compounds are useful for the treatment of RNA-dependent RNA viral infection. They are particularly useful as inhibitors of hepatitis C virus (HCV) NS5B polymerase, as inhibitors of HCV replication, and for the treatment of hepatitis C infection.
• HCV hepatitis C virus
• Hepatitis C virus is the leading cause of chronic liver disease throughout the world.
• the World Health Organization estimates that more than 170 million people worldwide (or about 3% of the world's population) are infected with the single-stranded ribonucleic acid (RNA) HCV.
• RNA ribonucleic acid
• RNA ribonucleic acid
• Approximately one-fifth of chronically infected patients with HCV will eventually develop cirrhosis of the liver, suffering considerable morbidity and mortality, including liver failure and hepatocellular carcinoma (TJ. Liang et al. Ann. Intern. Med.
• HCV infection is the primary indication for liver transplantation in the United States (NIH Consensus Statement on Management of Hepatitis C. 2002; http://www.ncbi.nlm.nih.gov/pubmed/14768714y
• HCV has been classified as a member of the virus family Flaviviridae that includes the genera flaviviruses, pestiviruses, and hapaceiviruses which includes hepatitis C viruses (Rice, C. M., Flaviviridae: The viruses and their replication. In: Fields Virology, Editors: B. N. Fields, D. M. Knipe and P. M. Howley, Lippincott-Raven Publishers, Philadelphia, Pa., Chapter 30, 931- 959, 1996).
• HCV is an enveloped virus containing a positive- sense single-stranded RNA genome of approximately 9.4 kb.
• the viral genome consists of a highly conserved 5' untranslated region (UTR), a long open reading frame encoding a polyprotein precursor of- approximately 3011 amino acids, and a short 3' UTR.
• HCV Hastolica virus
• Type Ib is the most prevalent subtype in Asia.
• X. Forns and J. Bukh Clinics in Liver Disease 1999 3:693-716; J. Bukh et al., Semin. Liv. Dis. 1995 15:41-63.
• Type 1 infectious is more resistant to therapy than either type 2 or 3 genotypes (N. N. Zein, Clin. Microbiol. Rev., 2000 13:223-
• the HCV genome encodes a polyprotein of 3010-3033, amino acids [Q. L. Choo, et al, Proc. Natl. Acad. Sci. USA, 1991 88:2451-2455; N. Kato et al., Proc. Natl. Acad. Sci. USA 1990 87:9524-9528; A. Takamizawa et al., J. Virol. 1991 65:1105-1113).
• Viral structural proteins include a nucleocapsid core protein (C) and two envelope glycoproteins, El and E2.
• HCV also encodes two proteases, a zinc-dependent metalloproteinase encoded by the NS2-NS3 region and a serine protease encoded in the NS3 region.
• the HCV NS3 protease is a serine protease that helps process the majority of the viral enzymes, and is thus considered essential for viral replication and infectivity. These proteases are required for cleavage of specific regions of the precursor polyprotein into mature peptides.
• Ribavirin (l-((2R,3R,4S,5R)-3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan-2-yl)- lH-[l,2,4]triazole-3-carboxylic acid amide; Virazole®) is a synthetic, non-interferon-inducing, broad-spectrum antiviral nucleoside analog. Ribavirin has in vitro activity against several DNA and RNA viruses including Flaviviridae (Gary L. Davis. Gastroenterology 2000 118:S104-
• ribavirin reduces serum amino transferase levels to normal in 40% of patients, it does not lower serum levels of HCV-RNA. Ribavirin also exhibits significant toxicity and is known to induce anemia. Viramidine is a ribavirin prodrug converted ribavirin by adenosine deaminase to in hepatocytes. (J. Z. Wu, Antivir. Chem. Chemother. 2006 17(l):33-9) Interferons (IFNs) have been available for the treatment of chronic hepatitis for nearly a decade. IFNs are glycoproteins produced by immune cells in response to viral infection.
• Type 1 includes several interferon alphas and one interferon beta
• type 2 includes interferon gamma.
• Type 1 interferons are produced mainly by infected cells and protect neighboring cells from de novo infection. IFNs inhibit viral replication of many viruses, including HCV, and when used as the sole treatment for hepatitis C infection, IFN suppresses serum HCV-RNA to undetectable levels. Additionally, IFN normalizes serum amino transferase levels. Unfortunately, the effects of IFN are temporary. Cessation of therapy results in a 70% relapse rate and only 10-15% exhibit a sustained viro logical response with normal serum alanine transferase levels. (Davis, Luke-Bakaar, supra)
• Combination therapy of HCV with ribavirin and interferon- ⁇ currently is the standard of care for treatment-na ⁇ ve patients HCV.
• Combining ribavirin and PEG-IFN (infra) results in a sustained viral response (SVR) defined as undetectable hepatitis C virus ribonucleic acid (HCV RNA) 24 weeks after completion of therapy (Fried MW, et al. N. Engl. J. Med. 2002 347:975- 982) in 54-56% of patients with type 1 HCV.
• SVR sustained viral response
• HCV RNA undetectable hepatitis C virus ribonucleic acid
• RNA-dependent RNA polymerase is absolutely essential for replication of the single-stranded, positive sense, RNA genome. This enzyme has elicited significant interest among medicinal chemists. There is currently no preventive treatment of Hepatitis C virus (HCV) and currently approved therapies, which exist only against HCV, are limited. Design and development of new pharmaceutical compounds is essential.
• HCV Hepatitis C virus
• the present invention provides a compound according to formula I, or a pharmaceutically acceptable salt thereof, wherein:
• R 1 is a heteroaryl radical selected from the group consisting of 2-oxo-l,2-dihydro- pyridin-3-yl, 3-oxo-3,4-dihydro-pyrazin-2-yl, 3-oxo-2,3-dihydro-pyridazin-4-yl, 2-oxo- 1 ,2-dihydro-pyrimidin-4-one-5-yl and 2,4-dioxo- 1 ,2,3,4-tetrahydro- pyrimidin-5-yl said heteroaryl being optionally substituted by halogen, Ci_6 alkyl, Ci_3 haloalkyl or Ci_6 alkoxy;
• R 2 is (hetero)aryl radical selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl said (hetero)aryl radical optionally independently substituted with one to three substitutents selected from the group consisting of hydroxy, Ci_6 alkoxy, Ci_6 alkyl, Ci_6 hydroxyalkyl, Ci_3 alkoxy-
• R 3 is hydrogen, hydroxy, Ci_3 hydroxyalkyl or cyano
• R 4 is hydrogen, Ci_6 alkyl, Ci_6 haloalkyl, Ci_6 alkoxy, Ci_6 haloalkoxy, halogen or
• R 4 and R 5a together are CH 2 -O and together with atoms to which they are attached form a 2,3-dihydrobenzofuran;
• R 5a , R 5b and R 5c ( ⁇ ) when taken independently are selected independently from Ci_ 3 alkyl, Ci_ 2 alkoxy, Ci_ 2 fluoroalkyl, hydroxy or halogen or (H) when taken together, R 5a and R 5b together are C2-4 methylene and R 5c is Ci_3 alkyl, Ci_2 alkoxy, Ci_2 fluoroalkyl or halogen, or
• R 6 or R 4 and R 5a together are CH 2 -O and together with atoms to wwhhiicchh they are attached for a 2,3-dihydro-benzofuran and R 5b and R 5c are Ci_3 alkyl;
• R 6 is hydrogen, fluorine or
• R 6 and R 5a together are CH 2 -O and together with atoms to which they are attached form a 2,3-dihydrobenzofuran;
• R a and R b are independently in hydrogen, Ci_6 alkyl, Ci_6 haloalkyl, Ci_6 acyl, Ci_6 alkylsulfonyl, Ci_6 haloalkylsulfonyl, C3-7 cycloalkylsulfonyl, C3-7 cycloalkyl-
• Ci_3 alkyl- sulfonyl Ci_6 alkoxy-Ci_6 alkylsulfonyl, sulfamoyl, Ci .3 alkylsulfamoyl, Ci .3 dialkylsulfamoyl, carbamoyl, Ci .3 alkylcarbamoyl or Ci .3 dialkylcarbamoyl; or,
• the present invention also provides a method for treating a disease caused by the
• HCV Hepatitis C Virus
• the present invention also provides a method for inhibiting replication of HCV in a cell by administering a compound according to formula I in an amount effective to inhibit HCV.
• the present invention also provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound according to formula I and at least one pharmaceutically acceptable carrier, diluent or excipient.
• a or “an” entity refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound.
• a compound refers to one or more compounds or at least one compound.
• the terms “a” (or “an”), “one or more”, and “at least one” can be used interchangeably herein.
• the phrase “as defined herein above” refers to the broadest definition for each group as provided in the Summary of the Invention or the broadest claim. In all other embodiments provided below, substituents which can be present in each embodiment and which are not explicitly defined retain the broadest definition provided in the Summary of the Invention.
• the terms “comprise(s)” and “comprising” are to be interpreted as having an open-ended meaning. That is, the terms are to be interpreted synonymously with the phrases “having at least” or “including at least”.
• the term “comprising” means that the process includes at least the recited steps, but may include additional steps.
• the term “comprising” means that the compound or composition includes at least the recited features or components, but may also include additional features or components.
• any variable e.g., R 1 , R 4a , Ar, X 1 or Het
• its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such compounds result in stable compounds.
• a bond drawn into ring system indicates that the bond may be attached to any of the suitable ring atoms.
• the term "optional” or “optionally” as used herein means that a subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
• “optionally substituted” means that the optionally substituted moiety may incorporate a hydrogen or a substituent.
• variable can be equal to any integer value of the numerical range, including the end-points of the range.
• variable can be equal to any real value of the numerical range, including the end-points of the range.
• a variable which is described as having values between 0 and 2 can be 0, 1 or 2 for variables which are inherently discrete, and can be 0.0, 0.1, 0.01, 0.001, or any other real value for variables which are inherently continuous.
• Tautomeric compounds can exist as two or more interconvertable species.
• Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms.
• Tautomers generally exist in equilibrium and attempts to isolate an individual tautomers usually produce a mixture whose chemical and physical properties are consistent with a mixture of compounds. The position of the equilibrium is dependent on chemical features within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates while; in phenols, the enol form predominates.
• the compounds of formula I may contain one or more chiral centers and therefore exist in two or more stereoisomeric forms.
• the racemates of these isomers, the individual isomers and mixtures enriched in one enantiomer, as well as diastereomers when there are two chiral centers, and mixtures partially enriched with specific diastereomers are within the scope of the present invention.
• substitution of the tropane ring can be in either endo- or exo-configuration, and the present invention covers both configurations.
• the present invention includes all the individual stereoisomers (e.g. enantiomers), racemic mixtures or partially resolved mixtures of the compounds of formulae I and, where appropriate, the individual tautomeric forms thereof.
• racemates can be used as such or can be resolved into their individual isomers.
• the resolution can afford stereochemically pure compounds or mixtures enriched in one or more isomers.
• Methods for separation of isomers are well known (cf. Allinger N. L. and Eliel E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) and include physical methods such as chromatography using a chiral adsorbent.
• Individual isomers can be prepared in chiral form from chiral precursors.
• individual isomers can be separated chemically from a mixture by forming diastereomeric salts with a chiral acid, such as the individual enantiomers of 10-camphorsulfonic acid, camphoric acid, .alpha.-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, and the like, fractionally crystallizing the salts, and then freeing one or both of the resolved bases, optionally repeating the process, so as obtain either or both substantially free of the other; i.e., in a form having an optical purity of >95%.
• the racemates can be covalently linked to a chiral compound
• the compounds of formula I may contain an acidic or basic functional groups. Suitable acid addition salts are formed by protonation of a basic center with an acid. Deprotonation of an acidic center by a base likewise forms a salt. Salt formation may confer a desirable pharmacokinetic property on the active ingredient which were absent in the non-salt form, and may even positively affect the pharmacodynamics of the active ingredient with respect to its therapeutic activity in the body.
• pharmaceutically acceptable salt of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
• Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic
• R 1 is 2-oxo-l,2-dihydro-pyridin-3-yl, 3-oxo-3,4-dihydro-pyrazin-2-yl, 3- oxo-2,3-dihydro-pyridazin-4-yl, and 2,4-dioxo-l,2,3,4-tetrahydro-pyrimidin-5-yl;
• R 2 is optionally substituted phenyl or optionally substituted pyridinyl;
• R 5a , R 5b and R 5c are (i) independently Ci_ 3 alkyl or Ci_ 3 haloalkyl or (H)
• R 5a and R 5b together are (CH 2 ) 2 and R 5c is Ci_ 3 alkyl, Ci_ 3 haloalkyl or halogen.
• R 1 is 2-oxo-l,2-dihydro-pyridin-3-yl, 3-oxo-3,4-dihydro-pyrazin-2-yl, 3- oxo-2,3-dihydro-pyridazin-4-yl, and 2,4-dioxo-l,2,3,4-tetrahydro-pyrimidin-5-yl;
• R 2 is phenyl or pyridinyl substituted at least by (CH 2 ) n NR a R b wherein n is 0 or 1 and R a is hydrogen and R b is Ci_6 sulfonyl, Ci_6 haloalkylsulfonyl, C 3 _7 cycloalkylsulfonyl, C 3 _7 cycloalkyl-Ci_ 3 alkyl-sulfonyl or Ci_6 alkoxy-Ci_
• R 1 is 2-oxo-l,2-dihydro-pyridin-3-yl or 3-oxo-2,3-dihydro-pyridazin 4-yl
• R 2 is phenyl or pyridinyl substituted at least by (CH 2 ) n NR a R b wherein n is 0 or 1 and R a is hydrogen and R b is Ci_6 sulfonyl, Ci_6 haloalkylsulfonyl, C 3 _7 cycloalkylsulfonyl, C 3 _7 cycloalkyl-Ci_ 3 alkyl-sulfonyl or Ci_6 alkoxy-Ci_6 alkylsulfonyl;
• R 4 is hydrogen or Ci_6 alkoxy
• R 3 is hydrogen or hydroxy
• R 5a , R 5b and R 5c are (i) independently Ci_ 3 alkoxy
• R 1 is 2-oxo-l,2-dihydro-pyridin-3-yl or 3-oxo-2,3-dihydro-pyridazin-4-yl
• R 2 is phenyl or pyridinyl substituted at least by (CH 2 ) n NR a R b wherein n is 0 or 1 and R a is hydrogen and R b is Ci_6 sulfonyl, Ci_6 haloalkylsulfonyl, C 3 _7 cycloalkylsulfonyl, C 3 _7 cycloalkyl-Ci_ 3 alkyl-sulfonyl or Ci_6 alkoxy-Ci_6 alkylsulfonyl; R 4 is hydrogen or Ci_6 alkoxy; R 3 is hydrogen or hydroxy; and R 5a , R 5b and R 5c are methyl.
• R 1 is 2-oxo-l,2-dihydro-pyridin-3-yl or 3-oxo-2,3-dihydro-pyridazin 4-yl
• R 2 is phenyl or pyridinyl substituted at least by (CH 2 ) n NR a R b wherein n is 0 or 1 and R a is hydrogen and R b is Ci_6 sulfonyl, Ci_6 haloalkylsulfonyl, C3_7 cycloalkylsulfonyl, C3_7 cycloalkyl-Ci_3 alkyl-sulfonyl or Ci_6 alkoxy-Ci_6 alkylsulfonyl;
• R 4 is hydrogen or Ci_6 alkoxy
• R 3 is hydrogen or hydroxy
• R 5a and R 5b together are (CH 2 ) 2 and R 5c is Ci_3
• R 1 is 2-oxo-l,2-dihydro-pyridin-3-yl or 3-oxo-2,3-dihydro- pyridazin 4-yl
• R 2 is phenyl or pyridinyl substituted at least by (CH 2 ) n NR a R b wherein n is 0 or 1 and R a is hydrogen and R b is Ci_6 sulfonyl, Ci_6 haloalkylsulfonyl, C3_7 cycloalkylsulfonyl, C3_7 cycloalkyl-Ci_3 alkyl-sulfonyl or Ci_6 alkoxy-Ci_6 alkylsulfonyl;
• R 4 is hydrogen or Ci_6 alkoxy
• R 3 is hydrogen or hydroxy
• R 5a and R 5b together are (CH 2 ) 2 and R 5c is
• R 1 is 2-oxo-l,2-dihydro-pyridin-3-yl or 3-oxo-2,3-dihydro- pyridazin 4-yl
• R 2 is pyrimidinyl, pyrazinyl and pyridazinyl substituted at least by (CH 2 ) n NR a R b wherein n is 0 or 1 and R a is hydrogen and R b is Ci_6 sulfonyl, Ci_6 haloalkylsulfonyl, C3_7 cycloalkylsulfonyl, C3-7 cycloalkyl-Ci_3 alkyl-sulfonyl or Ci_6 alkoxy-Ci_6 alkylsulfonyl; R 3 is hydrogen or hydroxy; R 4 is hydrogen or Ci_6 alkoxy; and, R 5a , R 5b and R 5c
• R 1 is optionally substituted 3-oxo-3,4-dihydro-pyrazin-2-yl, or 2,4-dioxo- l,2,3,4-tetrahydro-pyrimidin-5-yl
• R 2 is phenyl or pyridinyl substituted at least by (CH 2 ) n NR a R b wherein n is 0 or 1 and R a is hydrogen and R b is Ci_6 sulfonyl, Ci_6 haloalkylsulfonyl, C3_7 cycloalkylsulfonyl, C3-7 cycloalkyl-Ci_3 alkyl-sulfonyl or Ci_6 alkoxy-Ci_6 alkylsulfonyl; R 3 is hydrogen or hydroxy; R 4 is hydrogen or Ci_6 alkoxy; and R 5a , R 5b and R 5
• R 1 is optionally substituted 3-oxo-3,4-dihydro-pyrazin-2-yl, or 2,4-dioxo- l,2,3,4-tetrahydro-pyrimidin-5-yl
• R 2 is pyrimidinyl, pyrazinyl and pyridazinyl substituted at least by (CH 2 ) n NR a R b wherein n is 0 or 1 and R a is hydrogen and R b is Ci_ 6 sulfonyl, Ci_ 6 haloalkylsulfonyl, C3_7 cycloalkylsulfonyl, C3_7 cycloalkyl-Ci_3 alkyl-sulfonyl or Ci_6 alkoxy-Ci_6 alkylsulfonyl; R 3 is hydrogen or hydroxy; R 4 is hydrogen or Ci_6 alk
• R 1 is optionally substituted 2-oxo-l,2-dihydro-pyrimidin-4-one- 5-yl
• R 2 is phenyl or pyridinyl substituted at least by (CH2) n NR a R b wherein n is 0 or 1 and R a is hydrogen and R b is Ci_6 sulfonyl, Ci_6 haloalkylsulfonyl, C3_7 cycloalkylsulfonyl, C3_7 cycloalkyl-Ci_3 alkyl-sulfonyl or Ci_6 alkoxy-Ci_6 alkylsulfonyl;
• R 3 is hydrogen or hydroxy;
• R 4 is hydrogen or Ci_6 alkoxy;
• R 5a , R 5b and R 5c are (f) independently Ci_3 alkyl or Ci_3 haloalkyl or (U) R 5
• a method of treating a HCV infection in a patient in need thereof comprising administering a therapeutically effective amount of a compound according to formula I wherein R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 5c , R 6 , R a , R b and n are as defined hereinabove.
• a fourteenth embodiment of the present invention there is provided a method of treating a HCV infection in a patient in need thereof comprising co-administering a therapeutically effective amount of a compound according to formula I wherein R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 5c , R 6 , R a , R b and n are as defined herein above and at least one immune system modulator and/or at least one antiviral agent that inhibits replication of HCV.
• a method of treating a disease caused by HCV in a patient in need thereof comprising co-administering a therapeutically effective amount of a compound according to formula I wherein R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 5c , R 6 , R a , R b and n are as defined herein above and at least one immune system modulator selected from interferon, interleukin, tumor necrosis factor or colony stimulating factor.
• a method of treating a HCV infection in a patient in need thereof comprising co-administering a therapeutically effective amount of a compound according to formula I wherein R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 5c , R 6 , R a , R b and n are as defined herein above and an interferon or chemically derivatized interferon.
• a method of treating a HCV infection in a patient in need thereof comprising co-administering a therapeutically effective amount of a compound according to formula I wherein R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 5c , R 6 , R a , R b and n are as defined herein above and another antiviral compound selected from the group consisting of a HCV protease inhibitor, another HCV polymerase inhibitor, a HCV helicase inhibitor, a HCV primase inhibitor and a HCV fusion inhibitor.
• a method for inhibiting viral replication in a cell by delivering a therapeutically effective amount of a compound of the formula I wherein R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 5c , R 6 , R a , R b and n are as defined herein above admixed with at least one pharmaceutically acceptable carrier, diluent or excipient.
• composition comprising a compound according to formula I wherein R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 5c , R 6 , R a , R b and n are as defined herein above admixed with at least one pharmaceutically acceptable carrier, diluent or excipient.
• the present invention also provides the use of compounds of formula I for the manufacture of a medicament for treating a HCV infection.
• compounds of formula I as defined above and at least one immune system modulator and/or at least one antiviral agent that inhibits replication of HCV for the manufacture of a medicament for treating a HCV infection.
• alkyl as used herein without further limitation alone or in combination with other groups, denotes an unbranched or branched chain, saturated, monovalent hydrocarbon residue containing 1 to 10 carbon atoms.
• lower alkyl denotes a straight or branched chain hydrocarbon residue containing 1 to 6 carbon atoms.
• Ci-6 alkyl as used herein refers to an alkyl composed of 1 to 6 carbons.
• alkyl groups include, but are not limited to, lower alkyl groups include methyl, ethyl, propyl, ⁇ o-propyl, n-butyl, iert-butyi, tert-butyi, neopentyl, hexyl, and octyl.
• alkylaryl halo alky lheteroaryl
• arylalkylheterocyclyl alkylcarbonyl
• alkoxyalkyl alkylcarbonyl
• phenylalkyl refers to an alkyl group having one to two phenyl substituents, and thus includes benzyl, phenylethyl, and biphenyl.
• An "alky lamino alkyl” is an alkyl group having one to two alkylamino substituents.
• “Hydroxyalkyl” includes 2-hydroxyethyl, 2-hydroxypropyl, 1 -(hydro xymethyl)-2-methylpropyl, 2-hydroxybutyl, 2,3-dihydroxybutyl, 2-(hydroxymethyl), 3-hydroxypropyl, and so forth. Accordingly, as used herein, the term “hydroxyalkyl” is used to define a subset of heteroalkyl groups defined below.
• -(ar)alkyl refers to either an unsubstituted alkyl or an aralkyl group.
• (hetero)aryl or (hetero)aryl refers to either an aryl or a heteroaryl group.
• alkylene denotes a divalent saturated linear hydrocarbon radical of 1 to 10 carbon atoms (e.g., (CH 2 ) n )or a branched saturated divalent hydrocarbon radical of 2 to 10 carbon atoms (e.g., -CHMe- or -CH 2 CH(Z-Pr)CH 2 -), unless otherwise indicated.
• Co-4 alkylene refers to a linear or branched saturated divalent hydrocarbon radical comprising 1-4 carbon atoms or, in the case of Co, the alkylene radical is omitted. Except in the case of methylene, the open valences of an alkylene group are not attached to the same atom.
• alkylene radicals include, but are not limited to, methylene, ethylene, propylene, 2- methyl-propylene, 1,1-dimethyl-ethylene, butylene, 2-ethylbutylene.
• alkoxy as used herein means an -O-alkyl group, wherein alkyl is as defined above such as methoxy, ethoxy, n-propyloxy, z-propyloxy, n-butyloxy, z-butyloxy, t-butyloxy, pentyloxy, hexyloxy, including their isomers.
• “Lower alkoxy” as used herein denotes an alkoxy group with a "lower alkyl” group as previously defined.
• C 1 -K) alkoxy as used herein refers to an-O-alkyl wherein alkyl is C 1-10 .
• halo alkyl denotes an unbranched or branched chain alkyl group as defined above wherein 1, 2, 3 or more hydrogen atoms are substituted by a halogen.
• Examples are 1-fluoromethyl, 1-chloromethyl, 1-bromomethyl, 1-iodomethyl, difluoromethyl, trifluoromethyl, trichloromethyl, 1-fluoro ethyl, 1-chloroethyl, 1 2-fluoroethyl, 2-chloroethyl, 2- bromoethyl, 2,2-dichloroethyl, 3-bromopropyl or 2,2,2-trifluoroethyl.
• fluoroalkyl refers to a haloalkyl moiety wherein fluorine is the halogen.
• haloalkoxy refers to a group -OR where R is haloalkyl as defined herein.
• halo alky lthio refers to a group -SR where R is haloalkyl as defined herein.
• halogen or "halo” as used herein means fluorine, chlorine, bromine, or iodine.
• hydroxyalkyl and "alkoxyalkyl” as used herein denotes alkyl radical as herein defined wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl or alkoxy groups respectively.
• a Ci_3 alkoxy-Ci_6 alkyl moiety refers to a Ci_6 alkyl substituent in which 1 to 3 hydrogen atoms are replaced by a Ci_3 alkoxy and the point of attachment of the alkoxy is the oxygen atom.
• cyano refers to a carbon linked to a nitrogen by a triple bond, i.e., -C ⁇ N.
• nitro refers to a group -NO 2 .
• carboxy refers to a group -CO 2 H.
• Ci_3 alkylsulfonylamido refers to a group RSO 2 NH- wherein R is a Ci_3 alkyl group as defined herein.
• sulfamoyl refers to the radical -S(O) 2 NH 2 .
• N- alkylsulfamoyl and N, N-dialkylsulfamoyl refers to the radical -S(O) 2 NRR", wherein R' and R" are hydrogen and lower alkyl and R' and R" are independently lower alkyl respectively.
• Examples of N-alkylsulfamoyl substituents include, but are not limited to methylaminosulfonyl, ⁇ o-propylaminosulfonyl.
• N,N-dialkylsulfamoyl substituents include, but are not limited to dimethylaminosulfonyl, ⁇ o-propyl-methylaminosulfonyl.
• carbamoyl as used herein means the radical -CONH 2 .
• N- alkylcabamoyl and “N,N-dialkylcarbamoyl” means a radical CONHR' or CONRR" respectively wherein the R and R" groups are independently alkyl as defined herein.
• N- arylcabamoyl denotes the radical CONHR' wherein R' is an aryl radical as defined herein.
• (hetero)aryl refers to a ring which is either an aromatic ring or a hetero aromatic ring.
• 1 ,2-diarylcyclopropanes refers to all compounds encompassed in claim 1 without limitation.
• pyridine refers to a six-membered hetero aromatic ring with one nitrogen atom.
• pyrimidine pyrimidinyl
• pyrazine pyrazinyl
• pyridazine pyridazinyl
• the compounds of the present invention according to formula I are used in combination with other active therapeutic ingredients or agents to treat patients with an HCV viral infection.
• the active therapeutic ingredient used in combination with the compound of the present invention can be any agent having a therapeutic effect when used in combination with the compound of the present invention.
• the active agent used in combination with the compound of the present invention can be interferons, ribavirin analogs, HCV NS3 protease inhibitors, nucleoside inhibitors of HCV polymerase, non-nucleoside inhibitors of HCV polymerase, and other drugs for treating HCV, or mixtures thereof.
• nucleoside NS5b polymerase inhibitors examples include, but are not limited to
• Non-nucleoside NS5b polymerase inhibitors include, but are not limited to HCV- 796 (ViroPharma and Wyeth) ,MK-0608, MK-3281 (Merck), NM- 107, R7128 (R4048), VCH-759 (ViroChem), GSK625433 and GSK625433 (Glaxo), PF-868554 (Pfizer), GS-9190 (Gilead), A-837093 and A848837 (Abbot Laboratories), ANA598 (Anadys Pharmaceuticals); GLl 00597 (GNLB/NVS), VBY 708 (ViroBay), benzimidazole derivatives (H.
• Inhibitors of the HCV NS3 protease also have been identified as potentially useful for treatment of HCV.
• Protease inhibitors in clinical trials include VX-950 (Telaprevir, Vertex), SCH503034 (Broceprevir, Schering), TMC435350 (Tibotec/Medivir) and ITMN-191 (Intermune).
• protease inhibitors in earlier stages of development include MK7009 (Merck), BMS-605339 and BMS-790052 (Bristol Myers Squibb), VBY-376 (Virobay), IDXSCA/IDXSCB (Idenix), BI12202 and BILN-2065 (Boehringer-Ingelheim), VX-500 (Vertex), PHXl 766 Phenomix).
• interferons examples include, but are not limited to pegylated rIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b, rIFN-alpha 2a, consensus IFN alpha (infergen), feron, reaferon, intermax alpha, r-IFN-beta, infergen and actimmune, IFN-omega with DUROS, albuferon, locteron, Albuferon, Rebif, oral interferon alpha, IFNaIp ha-2b XL, AVI-005, PEG- Infergen, and pegylated IFN-beta.
• cyclophilin inhibitors which inhibit RNA binding to NS5b, nitazoxanide, Celgosivir (Migenix), an inhibitor of ⁇ - glucosidase-1, caspase inhibitors, To 11- like receptor agonists and immuno stimulants such as Zadaxin (SciClone).
• Ribavirin analogs and the ribavirin prodrug viramidine (taribavirin) have been administered with interferons to control HCV.
• TDMS saturated
• TDMS tert-butyldimethylsilyl or t-BuMe 2 Si
• Tf triflate or CF 3 SO 2 -
• Tf trifluoroacetic acid
• TLC thin layer chromatography
• THF tetrahydrofuran
• TEDA tetramethylethylenediamine
• TMS p-toluenesulfonic acid monohydrate
• TsOH or pTsOH 4-Me-C6H4SO 2 - or tosyl
• N-urethane-N-carboxyanhydride N-urethane-N-carboxyanhydride
• the starting materials and reagents used in preparing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, Volumes 1-21; R. C. LaRock, Comprehensive Organic Transformations, 2nd edition Wiley- VCH, New York 1999; Comprehensive Organic Synthesis, B. Trost and I. Fleming (Eds.) vol. 1-9 Pergamon, Oxford, 1991; Comprehensive Heterocyclic Chemistry, A. R. Katritzky and C. W. Rees (Eds) Pergamon, Oxford 1984, vol.
• the starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.
• the reactions described herein preferably are conducted under an inert atmosphere at atmospheric pressure at a reaction temperature range of from about -78 0 C to about 150 0 C, more preferably from about 0° C to about 125° C, and most preferably and conveniently at about room (or ambient) temperature, e.g., about 20° C.
• the 1 ,2-diarylcyclopropanes encompassed by the present invention can be prepared from A-2 which in turn is readily available from 3-te/t-butyl-2-hydroxy-benzaldehyde (A-Ia) by bromination of the 5-position with elemental bromine and subsequent alkylation of the phenol under basic conditions to afford A-2.
• Alkylation of phenol is typically carried out in solvents like DMF, THF, NMP, MeCN, acetone, DCM and DCE, at temperatures between 0 0 C and 100 0 C.
• bases typically used bases are K2CO3, sodium hydride, lithium hexamethyldisilazide, sodium hexamethyldisilazide and potassium hexamethyldisilazide.
• Alkylating agents such as alkyl halides, alkyl mesylates and alkyl triflates afford A-2.
• Coupling of the latent pyridone (or other heteroaryl group within the scope of the invention) and the aryl ring is accomplished by Suzuki coupling.
• SCHEME A depicts the coupling of 2-methoxy-pyridin-3-yl boronic acid (A-3, step 3). Subsequent cleavage of the O- Me bond (step 6) affords the desired pyridone.
• the Suzuki reaction is a palladium-catalyzed coupling of a boronic acid with an aryl or vinyl halide or triflate.
• Typical catalysts include Pd(PPtLs) 4 , PdCl2(dppf), Pd(OAc) 2 and PdCI 2 (PPlIs) 2 .
• PdCl 2 (dppf) primary alkyl borane compounds can be coupled to aryl or vinyl halide or triflate without ⁇ eto-elimination.
• the reaction can be carried out in a variety of organic solvents including toluene, THF, dioxane, DCE, DMF, DMSO and MeCN, aqueous solvents and under biphasic conditions.
• Reactions are typically run from about RT to about 150° C.
• Additives e.g., CsF, KF, TlOH, NaOEt and KOH
• CsF, KF, TlOH, NaOEt and KOH frequently accelerate the coupling.
• components in the Suzuki reaction such as the particular palladium catalyst, the ligand, additives, solvent, temperature, numerous protocols have been identified.
• Highly active catalysts have been described (see, e.g., J. P. Wolfe et ah, J. Am. Chem. Soc. 1999 121(41):9550-9561 and A. F. Littke et al., J. Am. Chem. Soc. 2000 122(17):4020- 4028).
• the coupling can also be carried out with B-(l,2-dihydro-2-oxo-3-pyridinyl)-boronic acid, B-(l,2,3,4-tetrahydro-2,4-dioxo-5- pyrimidinyl)-boronic acid and B-(2,3-dihydro-3-oxo-4-pyridazinyl)-boronic acid.
• B-(l,2-dihydro-2-oxo-3-pyridinyl)-boronic acid B-(l,2,3,4-tetrahydro-2,4-dioxo-5- pyrimidinyl)-boronic acid
• B-(2,3-dihydro-3-oxo-4-pyridazinyl)-boronic acid B-(2,3-dihydro-3-oxo-4-pyridazinyl)-boronic acid.
• the stilbene intermediates are prepared from A-4 employing a Wittig homologation with benzyl-triphenyl- ⁇ 5 -phosphane or a substituted analog thereof (step 4).
• the Wittig reaction is the reaction of an aldehyde or ketone with a triphenyl phosphonium ylide to afford an alkene and triphenylphosphine oxide.
• Wittig reactions are most commonly used to condense aldehydes or ketones to singly substituted phosphine ylides.
• the Wittig reagent is usually prepared from a phosphonium salt, which is, in turn, prepared by alkylation OfPh 3 P with an alkyl halide.
• a solvent such as Et 2 O or THF and a strong base such as phenyl lithium or n-butyllithium is added.
• the product is usually mainly the Z-isomer, although a lesser amount of the E- isomer also is often formed. This is particularly true when ketones are used. If the reaction is performed in DMF in the presence of LiI or NaI, the product is almost exclusively the Z-isomer. If the E-isomer is the desired product, the Schlosser modification may be used.
• the Homer- Wadsworth-Emmons reaction (B. E. Maryanoff and A. B. Reitz, Chem Rev. 1989 89:863-927) produces predominantly E-alkenes.
• the Homer- Wadsworth- Emmons reaction (HWE reaction) is the condensation of stabilized phosphonate carbanions with aldehydes (or ketones). In contrast to phosphonium ylides used in the Wittig reaction, phosphonate-stabilized carbanions are more nucleophilic and more basic.
• Compounds encompassed by the present invention wherein Ar is substituted can be prepared from benzyl ylides or diethyl benzylphosphonates which can be easily prepared from readily available benzyl halides.
• Sulfonamides encompassed within the scope of the claims are prepared by the HWE condensation of (4-nitro-benzyl)-phosphonic acid diethyl ester and A-4. Subsequent reduction of the nitro substituent affords an amine which can be concerted to a sulfonamide with mesyl chloride or with other readily available sulfonamides such as cycloalkylsulfonyl chlorides or haloalkylsulfonyl chlorides.
• Suitable reducing agents to convert the nitro group to the corresponding amine include, e.g., LiAlH 4 , LiBH 4 , Fe, Sn or Zn, in a reaction inert solvent, e.g.
• the cyclopropyl ring is introduced (step 5) by palladium acetate catalyzed cyclopropanation of A-5 with diazomethane.
• step 5 palladium acetate catalyzed cyclopropanation of A-5 with diazomethane.
• the preparation of compounds of the present invention substituted at the 2-position can be prepared by an analogous sequence starting with B-I.
• R 1 is a hydro xyl group
• the acidic phenol is conveniently protected as a benzyl ether.
• incorporation of the latent pyridone as a benzyloxy-pyridine allows concomitant removal of the two benzyl ethers and reduction of the olefin.
• incorporation of the latent pyridone as a methoxy-pyridine permits stepwise debenzylation and demethylation (see e.g., example 7)
• One skilled in the art will appreciate other functional groups can be used if desired.
• R 1 is alkoxy or substituted alkoxy within the scope of the present invention
• R 1 is alkoxy or substituted alkoxy within the scope of the present invention
• Conversion of B-3 to the final product is carried out as depicted in SCHEME A.
• R 1 is cyano
• R 1 is cyano
• A-2 can be converted to a boronic acid (ester) C-I and subjected to a Suzuki cross coupling with C-2 (a substituted 2-alkoxy-pyidine C-2 or a 3-halo-2-alkoxypyrazine wherein X is halo, trifluorosulfonyloxy or toluenesulfonyloxy) to afford C-3.
• C-2 a substituted 2-alkoxy-pyidine C-2 or a 3-halo-2-alkoxypyrazine wherein X is halo, trifluorosulfonyloxy or toluenesulfonyloxy
• An alternative route to 1,2-diarylcyclopropanes in the present invention utilizes a Stille palladium-catalyzed cross-couplings with 1 -[dibutyl-((£)-2-tributylstannanyl-vinyl)-stannanyl]- butane (D-7) as depicted in SCHEME D.
• Coupling of D-I and a pyridinyl-boronic acid under conditions described herein affords D-2a (see e.g. example 35 for the case wherein R 1 and R 3 are hydrogen).
• Sequential Stille-type couplings with D-7 initially afford D-3 which is subsequently coupled (step 4) with a substituted halo-(hetero)aryl compound such as 2-iodo-5- nitro -pyridine to afford the 1 ,2-diaryl-ethene D-4 which can converted to the corresponding cyclopropane.
• a substituted halo-(hetero)aryl compound such as 2-iodo-5- nitro -pyridine
• the penultimate target is a sulfonamide
• the nitro group is reduced to the amine and sulfonylated using standard methodology.
• heteroaryl rings can be introduced by coupling with intermediates such as 6-bromo- pyridazin-3-ylamine (CASRN 88497-27-2), 2-bromo-5-nitro-pyrazine (CASRN 117103-53-4) and 2-amino-5-iodo-pyrimidine (CASRN 1445-39-2).
• intermediates such as 6-bromo- pyridazin-3-ylamine (CASRN 88497-27-2), 2-bromo-5-nitro-pyrazine (CASRN 117103-53-4) and 2-amino-5-iodo-pyrimidine (CASRN 1445-39-2).
• the Stille cross-coupling reaction is a palladium-catalyzed coupling of an aryl or vinyl stannanes with aryl or vinyl halides or -sulfonyloxy compounds (J. K. Stille Angew. Chem. Int. Ed. 1986 25:508-524; A. F. Littke and G. C. Fu, Angew. Chem. Int. Ed. 1999, 38:2411-2413).
• Pd reagents including Pd(PPlIs) 4 , Pd(OAc) 2 and Pd 2 (dba)3 can be used.
• Phosphine ligands are useful rate accelerants if they are not a component of the palladium catalyst.
• the activity of the inventive compounds as inhibitors of HCV activity may be measured by any of the suitable methods known to those skilled in the art, including in vivo and in vitro assays.
• the HCV NS5B inhibitory activity of the compounds of formula I can determined using standard assay procedures described in Behrens et al, EMBO J. 1996 15:12- 22, Lohmann et al, Virology 1998 249:108-118 and Ranjith-Kumar et al, J. Virology 2001 75:8615-8623.
• the compounds of this invention have demonstrated in vitro HCV NS5B inhibitory activity in such standard assays.
• the HCV polymerase assay conditions used for compounds of the present invention are described in Example 3.
• Inhibition of recombinant purified HCV polymerase with compounds in vitro biochemical assays may be validated using the replicon system whereby the polymerase exists within a replicase complex, associated with other viral and cellular polypeptides in appropriate stoichiometry. Demonstration of cell-based inhibition of HCV replication may be more predictive of in vivo function than demonstration of HCV NS5B inhibitory activity in vitro biochemical assays
• the compounds of the present invention may be formulated in a wide variety of oral administration dosage forms and carriers.
• Oral administration can be in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions, syrups, or suspensions.
• Compounds of the present invention are efficacious when administered by other routes of administration including continuous (intravenous drip) topical parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include a penetration enhancement agent), buccal, nasal, inhalation and suppository administration, among other routes of administration.
• the preferred manner of administration is generally oral using a convenient daily dosing regimen which can be adjusted according to the degree of affliction and the patient's response to the active ingredient.
• a compound or compounds of the present invention, as well as their pharmaceutically useable salts, together with one or more conventional excipients, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages.
• the pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
• compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use.
• a typical preparation will contain from about 5% to about 95% active compound or compounds (w/w).
• preparation or “dosage form” is intended to include both solid and liquid formulations of the active compound and one skilled in the art will appreciate that an active ingredient can exist in different preparations depending on the target organ or tissue and on the desired dose and pharmacokinetic parameters.
• excipient refers to a compound that is useful in preparing a pharmaceutical composition, generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use.
• the compounds of this invention can be administered alone but will generally be administered in admixture with one or more suitable pharmaceutical excipients, diluents or carriers selected with regard to the intended route of administration and standard pharmaceutical practice.
• “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for human pharmaceutical use.
• Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
• a solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
• the carrier In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component.
• the active component In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
• Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
• Solid form preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
• Liquid formulations also are suitable for oral administration include liquid formulation including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions. These include solid form preparations which are intended to be converted to liquid form preparations shortly before use. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents.
• viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents.
• the compounds of the present invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
• the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol.
• oily or nonaqueous carriers, diluents, solvents or vehicles examples include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents.
• the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
• the compounds of the present invention may be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch.
• Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
• Lotions may be formulated with an aqueous or oily base and will in general also containing one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
• Formulations suitable for topical administration in the mouth include lozenges comprising active agents in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
• the compounds of the present invention may be formulated for administration as suppositories.
• a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify.
• the compounds of the present invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
• the compounds of the present invention may be formulated for nasal administration.
• the solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or spray.
• the formulations may be provided in a single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.
• the compounds of the present invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration.
• the compound will generally have a small particle size for example of the order of five (5) microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.
• the active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluoro carbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas.
• CFC chlorofluoro carbon
• the aerosol may conveniently also contain a surfactant such as lecithin.
• the dose of drug may be controlled by a metered valve.
• the active ingredients may be provided in a form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP).
• a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP).
• the powder carrier will form a gel in the nasal cavity.
• the powder composition may be presented in unit dose form for example in capsules or cartridges of e.g., gelatin or blister packs from which the powder may be administered by means of an inhaler.
• formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient.
• the compounds of the present invention can be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with a treatment regimen is crucial.
• Compounds in transdermal delivery systems are frequently attached to an skin-adhesive solid support.
• the compound of interest can also be combined with a penetration enhancer, e.g., Azone (1-dodecylaza- cycloheptan-2-one).
• Sustained release delivery systems are inserted subcutaneously into to the subdermal layer by surgery or injection.
• the subdermal implants encapsulate the compound in a lipid soluble membrane, e.g., silicone rubber, or a biodegradable polymer, e.g., polylactic acid.
• Suitable formulations along with pharmaceutical carriers, diluents and excipients are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania.
• a skilled formulation scientist may modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration without rendering the compositions of the present invention unstable or compromising their therapeutic activity.
• the modification of the present compounds to render them more soluble in water or other vehicle may be easily accomplished by minor modifications (salt formulation, esterification, etc.), which are well within the ordinary skill in the art.
• terapéuticaally effective amount means an amount required to reduce symptoms of the disease in an individual.
• the dose will be adjusted to the individual requirements in each particular case. That dosage can vary within wide limits depending upon numerous factors such as the severity of the disease to be treated, the age and general health condition of the patient, other medicaments with which the patient is being treated, the route and form of administration and the preferences and experience of the medical practitioner involved.
• a daily dosage of between about 0.01 and about 1000 mg/kg body weight per day should be appropriate in monotherapy and/or in combination therapy.
• a preferred daily dosage is between about 0.1 and about 500 mg/kg body weight, more preferred 0.1 and about 100 mg/kg body weight and most preferred 1.0 and about 10 mg/kg body weight per day.
• the dosage range would be about 7 mg to 0.7 g per day.
• the daily dosage can be administered as a single dosage or in divided dosages, typically between 1 and 5 dosages per day. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect for the individual patient is reached.
• One of ordinary skill in treating diseases described herein will be able, without undue experimentation and in reliance on personal knowledge, experience and the disclosures of this application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease and patient.
• the active compound or a salt can be administered in combination with another antiviral agent such as ribavirin, a nucleoside HCV polymerase inhibitor, another HCV non-nucleoside polymerase inhibitor or HCV protease inhibitor.
• another antiviral agent such as ribavirin, a nucleoside HCV polymerase inhibitor, another HCV non-nucleoside polymerase inhibitor or HCV protease inhibitor.
• the activity may be increased over the parent compound.
• the treatment is combination therapy, such administration may be concurrent or sequential with respect to that of the nucleoside derivatives.
• Concurrent administration as used herein thus includes administration of the agents at the same time or at different times. Administration of two or more agents at the same time can be achieved by a single formulation containing two or more active ingredients or by substantially simultaneous administration of two or more dosage forms with a single active agent.
• references herein to treatment extend to prophylaxis as well as to the treatment of existing conditions.
• treatment also includes treatment or prophylaxis of a disease or a condition associated with or mediated by HCV infection, or the clinical symptoms thereof.
• terapéuticaally effective amount means an amount required to reduce symptoms of the disease in an individual.
• the dose will be adjusted to the individual requirements in each particular case. That dosage can vary within wide limits depending upon numerous factors such as the severity of the disease to be treated, the age and general health condition of the patient, other medicaments with which the patient is being treated, the route and form of administration and the preferences and experience of the medical practitioner involved.
• a daily dosage of between about 0.01 and about 1000 mg/kg body weight per day should be appropriate in monotherapy and/or in combination therapy.
• a preferred daily dosage is between about 0.1 and about 500 mg/kg body weight, more preferred 0.1 and about 100 mg/kg body weight and most preferred 1.0 and about 10 mg/kg body weight per day.
• the dosage range would be about 7 mg to 0.7 g per day.
• the daily dosage can be administered as a single dosage or in divided dosages, typically between 1 and 5 dosages per day. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect for the individual patient is reached.
• One of ordinary skill in treating diseases described herein will be able, without undue experimentation and in reliance on personal knowledge, experience and the disclosures of this application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease and patient.
• a therapeutically effective amount of a compound of the present invention, and optionally one or more additional antiviral agents is an amount effective to reduce the viral load or achieve a sustained viral response to therapy.
• Useful indicators for a sustained response, in addition to the viral load include, but are not limited to liver fibrosis, elevation in serum transaminase levels and necro inflammatory activity in the liver.
• a marker is serum alanine transminase (ALT) which is measured by standard clinical assays.
• an effective treatment regimen is one which reduces ALT levels to less than about 45 ILVmL serum.
• the modification of the present compounds to render them more soluble in water or other vehicle may be easily accomplished by minor modifications (salt formulation, esterification, etc.), which are well within the ordinary skill in the art. It is also well within the ordinary skill of the art to modify the route of administration and dosage regimen of a particular compound in order to manage the pharmacokinetics of the present compounds for maximum beneficial effect in patients.
• step 1 To a slurry of NaH (0.38 g, 9.46 mmol) and 15-crown-5 (0.17 g, 0.79 mmol) in THF (5 mL) cooled to 0 0 C was added slowly a solution of diethyl (4-nitro-benzyl)-phosphonate (2.58 g, 9.46 mmol) and THF (8 mL). The resulting solution was stirred at 0 0 C until the bubbling ceased. To the resulting solution maintained at 0 0 C was added slowly a solution of 20 (1.90 g, 7.88 mmol) and THF (20 mL). The reaction was stirred at 0 0 C for 20 min then quenched with H 2 O.
• step 2 To a solution of 22 (1.0 g, 2.77 mmol), Pd(OAc) 2 (0.10 g) and DCM (10 mL) cooled to 0 0 C was added dropwise an ethereal solution of diazomethane (10 equivalents). After bubbling ceased the reaction was quenched with HOAc (10 equivalents) and the resulting solution washed with sat'd. aq. NaHCO 3 . The organic phase was dried (Na 2 SO 4 ), filtered and evaporated. The crude product was purified by SiO 2 chromatography eluting with 10% EtOAc/hexane to afford 0.986 g of 24 as a yellow oil.
• step 3 A microwave vial was charged with 24 (0.16 g, 0.427 mmol), 2-methoxy-pyridin- 3-yl boronic acid (23, 0.13 g, 0.855 mmol), Na 2 CO 3 (0.14 g, 1.22 mmol), Pd(PPh 3 ) 4 (0.1 g, 0.04 mmol) and a mixture of DCM and MeOH, sealed and irradiated in a microwave synthesizer at 115 0 C for 35 min. The solution was cooled, filtered and concentrated in vacuo. The crude product was purified by SiO 2 chromatography eluting with an EtOAc/hexane gradient (0 to 10% EtOAc) to afford 0.14 g of 26a.
• step 4 A suspension of 26a (0.14 g, 0.348 mmoL) and aqueous MeOH (6 mL 1 :1) was heated at reflux. To the suspension was added NH 4 Cl (0.19 g, 3.478 mmol) followed by Fe powder (0.10 g 1.739 mmol). The solution was heated at reflux for 2 h, cooled and filtered. The filtrate was concentrated in vacuo. The filtrate was taken up in EtOAc, sequentially washed with H 2 O and brine, dried (Na 2 SO 4 ), filtered and evaporated. The crude product was purified by SiO 2 chromatography eluting with 30% EtOAc/hexane to afford 0.10 g (77%) of 26b.
• step 5 To a solution of 26b ((0.10 g, 0.268 mmol) in pyridine (3 mL) was added mesyl chloride (31 ⁇ L, 0402 mmol) and the resulting solution stirred for 1 h. The reaction mixture was diluted with EtOAc and washed sequentially with aqueous CuSO 4 , 2N HCl and sat'd. NaHCO 3 . The organic phase was dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The crude product was purified by SiO 2 chromatography eluting with an EtOAc/hexane gradient (20 to 50%% EtOAc) to afford 0.14 g of 26c.
• step 6 A solution of 26c (0.14 g, 0.30 mmol), HOAc (3 mL) and HBr (105 ⁇ L) was heated ar 50 0 C for 2 d.
• the reaction mixture was cooled to RT, diluted with EtOAc and washed sequentially with H 2 O and sat'd. NaHCO 3 .
• the organic phase was dried (Na 2 SO 4 ), filtered and concentrated in vacuo.
• the crude product was purified by SiO 2 chromatography eluting with a gradient of DCM and a solution of DCM/MeOH/NH 4 OH (60:10:1) (70 to 20% DCM) to afford 80 mg ofl-l.
• step 2 A mixture of 28b (3.83 g), MeI (2.32 mL) and K 2 CO 3 (6.18 g ) in DMF (50 mL) was heated at 50 0 C for 1 h then cooled to RT and diluted with ether and water. The organic layer was thrice washed with water then brine, dried (MgSO 4 ) and concentrated to afford 3.99 g of 30 as a yellow solid.
• step 3 A sealed tube containing 30 (1.08 g), 23 (0.91 g), Na 2 CO 3 (1.05 g) and Pd(PPh 3 ) 4 (460 mg) in a mixture of MeOH (20 mL) and DCM (5 mL) was irradiated in a microwave reactor at 120° C for 30 min. The organic volatiles were removed under reduced pressure. The residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried (Na 2 SO 4 ), filtered and concentrated. The crude residue was purified by SiO 2 chromatography eluting with an EtOAc/hexane gradient (0 to 20% EtOAc) to afford 300 mg of 32.
• step 4 - 9 The conversion of 32 to 1-2 (steps 4 - 9) was carried out in accord with the procedures described in steps 1-6 of example 1 to afford 1-2 as a mixture of cis and trans isomers.
• 2-benzyloxy-pyridin-3-yl boronic acid (34) A solution of 2-benzyloxy-3-bromo-pyridine (2.50 g, 9.47 mmol), Pd(II)Cl 2 (PPh 3 ) 2 (232 mg, .28 mmol), KOAc (2.32 g, 23.67 mmol), bis- (pinacolato)diborane (2.95 g, 11.36 mmol) and DME (75 mL) was heated at 70 0 C for 26 h. The reaction mixture was cooled and partitioned between Et 2 O and water. The organic phase was separated, dried and evaporated.
• step 1 Benzylation of 3-bromo-5-te/t-butyl-2-hydroxy benzaldehyde (36a) with benzyl bromide is accomplished treating 36a with benzyl bromide and tetrabutylammonium hydroxide in a biphasic system comprised of MeOH and DCM to afford 2-benzyloxy-3-bromo-5-te/t-butyl- benzaldehyde (36b).
• step 2 A microwave vial was charged with 36b (1.5 g, 4.31 mmol), 34 (1.28 g, 5.60 mmol), Pd(PPh 3 ) 4 (0.5 g, 0.43 mmol) and Na 2 CO 3 (1.37 g, 12.93 mmol), flushed with argon and sealed. To the tube was added MeOH (2.5 mL) and DCM (7.5 mL) and the resulting to 120 0 C for 35 min. The reaction mixture was cooled to RT, filtered and concentrated in vacuo. The crude product was purified by SiO 2 chromatography eluting with 5% EtOAc/hexane to afford of 38a.
• step 3- To a solution of 38a (1.11 g, 2.46 mmol) in MeOH (20 mL) cooled to -78° C, was added a solution of sodium methoxide (0.5M in MeOH, 9.84 mL, 4.92 mmol) followed by dropwise addition of a solution of dimethyl l-diazo-2-oxopropylphoshonate (610 mg, 4.92 mmol) in MeOH (5 mL). The resulting reaction mixture was gradually warmed to RT and stirred overnight then quenched with a saturated aqueous NaHCO 3 . The organic volatiles were removed under reduced pressure. The crude residue was partitioned between EtOAc and saturated aqueous NaHCO 3 . The organic layer was washed with water, brine, and dried (Na 2 SO 4 ), filtered and concentrated. The crude residue was purified by SiO 2 chromatography eluting with 5% EtOAc/hexane to afford 38b.
• sodium methoxide 0.5M
• step 4 A round-bottom flask was charged with 38b (2 g, 4.47 mmol), AIBN (0.29 g) and benzene (20 mL) then flushed with argon then tributyl tin hydride (1.56 mL, 5.81 mmol) was added. The reaction mixture was heated at reflux for 3 h, cooled and concentrated in vacuo. The crude product was purified by SiO 2 chromatography eluting with 5% EtOAc/hexane to afford 38c.
• step 5 To a solution of Pd 2 (dba)3 (0.104 g, 0.11 mmol) and DMF (10 mL) maintained under an Ar atmosphere was added £r ⁇ -(2-furyl)phosphine (0.106 g, 0.45 mmol). After stirring the solution for 10 min the solution was added to a solution of 38c (2.8 g, 3.79 mmol), 2-iodo-5- nitro-pyridine (1.14 g, 4.55 mmol), LiCl (0.329 g, 7.58 mmol) and DMF (10 mL) which was maintained under an Ar atmosphere. The resulting solution was heated at 90 0 C overnight, cooled, then partitioned between EtOAc and aq. NH 4 Cl.
• step 6 - The cyclopropanation of 40 was carried out in accord with the procedure described in step 2 of example 1.
• the crude product was purified by SiO 2 chromatography eluting with a 5% EtOAc/hexane gradient to afford 42a.
• step 7 - To a solution of 42a (0.080 g) in EtOH (3.0 mL) was added Rainy-nickel (ca. 0.3 mL of a aqueous slurry) and the resulting solution stirred under an H 2 atmosphere (H 2 balloon) for 1 h. The solution was filtered and the filtrate concentrated in vacuo and purified on a SiO 2 column eluting with 40% EtOAc/hexane to afford 42b.
• Rainy-nickel ca. 0.3 mL of a aqueous slurry
• step 8 - Conversion of 42b to the methanesulfonamide 42c was carried out in accord with the procedure described in step 5 of example 1.
• step 9 Conversion of 42c to 1-4 was carried out in accord with the procedure described in step 6 of example 1.
• the reaction was heated at 65 0 C overnight.
• the crude product was purified on a preparative SiO 2 TLC plate developed with 10% MeOH/DCM to afford 1-4.
• the utilization of the Stille coupling to incorporate a pyridine ring as depicted in example 3 can be adapted to introduction of a pyrazine, pyridazine or pyrimidine ring.
• step 1 To a solution of 15-crown-5 in THF (20 mL) cooled to 0 0 C was added NaH (1.56 g,
• step 2 To a solution of 44a (0.460 g, 1.22 mmol) and AcCl (96.3 ⁇ L, 1.35 mmol) in DCM (10 mL) cooled to 0 0 C was added dropwise TEA (220 ⁇ L, 1.3 equivalents). After 2 h at RT the reaction mixture was partitioned between IN HCl and EtOAc. The aqueous phase was extracted with EtOAc and the combined EtOAc extracts were dried, filtered and concentrated in vacuo. The crude product was purified by SiO 2 chromatography eluting with 5% EtOAc/hexane to afford 44b.
• step 3 The cyclopropanation of 44b was carried out in accord with the procedure described in step 2 of example 1. The crude product was purified by SiO 2 chromatography eluting with a 5% EtOAc/hexane gradient to afford 46.
• step 4 To a solution of 46 (0.370 g) in MeOH (2.0 mL) and THF (2.0 mL) was added 2N NaOH (2.0 mL). After stirring for 1 h at RT the reaction was poured into IN HCl and the resulting solution extracted with EtOAc. The combined extracts were dried, filtered and concentrated in vacuo. The crude product was purified by SiO 2 chromatography eluting with 5% EtOAc/hexane to afford 48a.
• step 5 To a solution of 48a (0.340 g, 0.87 mmol) in EtOAc (10 mL) was added SnCl 2 -2H 2 O (0.98 g, 4.37 mmol). The resulting solution was heated at reflux for 2.5 h than cooled and poured into sat'd. aq. NaHCO 3 . The resulting solution was extracted with EtOAc and the combined extracts dried, filtered and concentrated in vacuo. The crude product was purified by SiO 2 chromatography eluting with 30% EtOAc/hexane to afford 48b.
• step 6 The conversion of 48b to the methanesulfonamide 48c was carried out in accord with the procedure described in step 5 of example 1.
• step 7 The conversion of 48c to 50 was carried out in accord with the procedure described in step 3 of example 1.
• the crude product was purified by SiO 2 chromatography eluting with 30% EtOAc/hexane.
• step 8 - The conversion of 50 to 1-3 was carried out in accord with the procedure described in step 6 of example 1.
• the crude product was purified by on a preparative SiO 2 TLC plate developed with 70% EtOAc/hexane followed by 5% MeOH/DCM.
• step 2 A microwave vial was charged with 52b (0.400 g, 3 mmol), ⁇ -(pinacolato)diboron (0.934 g, 4 mmol), dicyclohexyl[2',4',6'-tr ⁇ (l-methylethyl)[l,l'-biphenyl]-2-yl]-phosphine (X- Phos, 0.058 g, 0.12 mmol), Pd 2 (dba) 3 (0.056 g, 0.061 mmol) and KOAc (0.902 g, 9 mmol) and the flask was evacuated and back-filled with Ar and sealed.
• step 3 A microwave vial is charged with 24, 54 (2 equivalents), Na 2 CO 3 (2.8 equivalents), Pd(PPh 3 ) 4 (0.01 equivalents) and a mixture of DCM and MeOH, is sealed and irradiated in a microwave synthesizer at 115 0 C for 35 min. The solution is cooled, then filtered and concentrated in vacuo. The crude product is purified by SiO 2 chromatography eluting with an EtOAc/hexane gradient to afford of 56a. Reduction of the nitro group and sulfonylation of the resulting amine is carried out in accord with the procedures described in steps 4 and 5 of Example 1 to afford 56c.
• N-(4- ⁇ 2-[5-tert-Butyl-2-hydroxy-3-(3-oxo-2,3-dihydro-pyridazin-4-yl)-phenyl]- cyclopropyl ⁇ -phenyl)-methanesulfonamide (58) is prepared by Suzuki coupling of 54 and 48c in accord with the procedure described in step 3 of the present example.
• step 1 A mixture 30 (0.60 g CASRN 417715-878), 6 ⁇ -(pinacolato)diboron (31, 0.69 g), Pd(dppf) 2 Cl 2 (54 mg) and KOAc (542 mg) in DME (30 mL) under an argon atmosphere was heated at 70° C for 14 h and then at 90° C for additional 7 h. The reaction was cooled to RT, and diluted with water and ether. The organic layer was washed with brine, dried (MgSO 4 ), filtered and concentrated. The crude residue was purified by SiO 2 chromatography eluting with a EtOAc/hexane gradient (0 to 12% EtOAc) to afford 478 mg of 62 contaminated with a small amount of 31.
• step 2 A vial was charged with 62 (0.365 g 1.48 mmol), 2-chloro-3-methoxy-pyrazine (0.198 g, 1.370 mmol), Pd(Ph 3 ) 4 (0.106 g, 0.092 mmol) Na 2 CO 3 (0.313 g, 2.953 mmol), MeOH (6 mL) and DCM (2 mL), sealed and irradiated in a microwave synthesizer at 115 0 C for 30 min. The reaction mixture was cooled to RT, diluted with EtOAc, washed with brine, dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The crude product was purified by SiO 2 chromatography eluting with a EtOAc/hexane gradient (2 to 10% EtOAc) to afford 0.275 g of 64.
• step 3 To a solution of 4-nitro-benzylphosphonium bromide (1.23 g, 2.573 mmol) and DMF (10 mL) cooled to 0 0 C was added NaH (0.211 g, 5.275 mmol, 60% mineral oil dispersion). The solution was stirred for 30 min then a solution of 64 (0.251 g, 0.857 mmol) and DMF (5 mL) was added and the resulting solution stirred overnight at RT. The reaction was quenched by addition of IN HCl (8 mL) and the resulting solution diluted with EtOAc. The EtOAc solution was separated and twice washed with brine, dried (Na 2 SO 4 ), filtered and concentrated in vacuo.
• step 5 Reduction of the amine (step 5), conversion of the amine to the methanesulfonamide (step 6) is carried out in accord with steps 4 and 5 of example 1 to afford N-(4- ⁇ 2-[3-t ⁇ t-butyl-2- methoxy-5 -(3 -methoxy-pyrazin-2-yl)-phenyl] -cyclopropyl ⁇ -phenyl)-methanesulfonamide (66c) .
• step 1 To a solution of 2-(l-methylcyclopropyl)phenol (70, 0.55 g, 3.4 mmol; CASRN
• step 2 To a solution 72 (0.34 g, 1.9 mmol) in DCM-MeOH (3:2, 20 mL) was added tetrabutylammonium tribromide (0.98 g, 2.0 mmol) and the resulting mixture was stirred at RT for 75 min. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and water. The EtOAc layer was washed sequentially with water and brine, dried (Na 2 SO 4 ), filtered and concentrated.
• step 3 To a solution of 74a (0.44 g, 1.7 mmol) in DMF (4 mL) was added K 2 CO 3 (0.60 g, 4.4 mmol) and iodomethane (0.32 g, 2.3 mmol). The resulting mixture was stirred at 60° C for 2 h. The reaction mixture was cooled to RT and partitioned between water and Et 2 O. The organic layer was washed sequentially with water and brine, dried (Na 2 SO 4 ), filtered and concentrated to afford 0.47 g (96%) of 5-bromo-2-methoxy-3-(l-methylcyclopropyl)benzaldehyde(74b) as a light yellow solid.
• step 4 Sodium hydride (60% dispersion, 0.10 g, 2.6 mmol) and 15-crown-5 (0.038 g, 0.17 mmol) were added to THF (5 mL) at 0° C and stirred for 5 min. To the reaction mixture was then added dropwise over 5 min a solution of diethyl (4-nitrobenzyl)phosphonate (0.52 g, 1.9 mmol) in THF (5 mL), and stirring was continued at 0° C for 5 min. To this reaction mixture was then added dropwise over 10 min a solution of 76 (0.47 g, 1.7 mmol) in THF (10 mL). The reaction mixture was stirred for 30 min at 0° C then for 90 min at RT.
• step 5 Introduction of the cyclopropyl group to afford 5-bromo-2-methoxy-l-(l-methyl- cyclopropyl)-3-[(E)-2-(4-nitro-phenyl)-vinyl]-benzene (76) is carried out in accord with the procedure described in step 2 of example 1.
• reaction mixture Upon reaching an internal temperature of 19 0 C, the reaction mixture was cooled to 0 0 C, and B(OMe)3 (4.0 g, 39 mmol) was added dropwise over 15 min. After the addition was complete, the reaction mixture was warmed to RT and was stirred for 15 h. The mixture was then cooled to 0° C and a small amount of ice was added followed by 2M aqueous HCl (100 mL). The THF was removed under reduced pressure, and the aqueous solution was washed twice with DCM. Concentrated aqueous NaOH was added slowly until pH 5 was attained and a precipitate formed. The mixture was cooled to 0° C and stirred for 10 min.
• step 6 Reduction of the amine (step 6), conversion of the amine to the methanesulfonamide (step 7) is carried out in accord with steps 4 and 5 of example 1 to afford N-(4- ⁇ 2-[5-bromo-2-methoxy- 3 -( 1 -methyl-cyclopropyl)-phenyl] -cyclopropyl ⁇ -phenyl)-methanesulfonamide (66c) .
• Palladium- catalyzed cross-coupling of 80 and 66c to the title compound (step 8) is carried out in accord with step 3 of example 1 to afford the title compound.
• step 1 To a solution of 80 (2.457 g, 14 mmol) and acetone (75 mL) was added K2CO3
• step 2 To a solution of 82 (3.33 g, 15 mmol) and benzene (150 mL) in a dried flask was added sequentially Bu 3 SnH (6.625 g, 22 mmol) and AIBN (0.241 g) and the resulting solution heated at reflux overnight. The reaction mixture was cooled to RT, a 10% KF solution was added and the resulting two-phase mixture stirred vigorously for 2 h. The phases were separated and the organic phase was sequentially washed with sat'd NaHCO 3 (50 mL) and brine. The combined organic extracts were dried (Na 2 SO 4 ), filtered and evaporated. The crude product was purified by SiO 2 chromatography eluting with a DCM/hexane gradient (0 to 10% DCM) to afford 1.855 g (85%) of 84.
• step 3 To a solution of iodine (2.055 g, 8 mmol) and EtOH (30 mL) was added a solution of silver sulfate (2.525 g, 8 mmol) and a solution of 84 (1.200 g, 8 mmol) in EtOH (10 mL). The brown solution was stirred for 2.5 h at RT. The resulting suspension was filtered through CELITE, the pad rinsed with EtOH and the filtrate concentrated. The crude product was purified by SiO 2 chromatography eluting with a DCM/hexane gradient (0 to 10% DCM) to afford 2.001 g (90.5%) of 86.
• step 4 To a solution of 86 (2.00 g, 7 mmol) and HOAc (18 mL) in a dried flask was cooled to 0 0 C and Br 2 was added dropwise over 10 min. The reaction was stirred at RT overnight. Excess bromine was quenched with 10% aq. Na 2 S 2 O 3 (20 mL) and the HOAc was evaporated. The residue was extracted with Et 2 O and the organic extract washed with sat'd. NaHCO 3 . The aqueous phase was back-extracted with Et 2 O and the combined extracts washed sequentially with NaHCO 3 (2 x 20 mL), H 2 O and brine, dried (Na 2 SO 4 ), filtered and concentrated. The residue was purified by SiO 2 chromatography eluting with a DCM/hexane gradient (0 to 10% DCM) to afford 1.5960 g (71.5%) of 88.
• step 5 A microwave tube was charged with 88 ( 0.068 g), 89 (0.078 g), Na 2 CO 3 (0.064 g), Pd(PPh 3 ) 4 (0.023 g), MeOH (1.8 mL) and DCM (0.6 mL). The tube was flushed with argon, sealed and irradiated in a microwave synthesizer at 125 0 C for 40 min. The reaction mixture was cooled and concentrated in vacuo. The residue was partitioned between DCM (25 mL) and H 2 O (5 mL). The organic layer was washed with brine (5 mL). The aqueous phase was twice extracted with DCM (25 mL).
• step 6 Introduction of the cyclopropyl group is carried out in accord with the procedure described in step 2 of example 1 to afford 92.
• Introduction of the pyridazinone ring (step 7) is accomplished by coupling 54 and 92 in accord with the procedure in step 3 of example 5 to afford 100.
• RNA product generated by NS5B570-Conl at the end of the reaction was directly proportional to the amount of light emitted by the scintillant.
• the N-terminal 6-histidine tagged HCV polymerase derived from HCV Conl strain, genotype Ib (NS5B570n-Conl) contains a 21 amino acid deletion at the C-terminus relative to the full-length HCV polymerase and was purified from E. coli strain BL21(DE) pLysS.
• the construct, containing the coding sequence of HCV NS5B Conl was inserted into the plasmid construct pET17b, downstream of a T7 promoter expression cassette and transformed into E. coli.
• NS5B570n-Conl was purified to homogeneity using a three-step protocol including subsequent column chromatography on Ni- NTA, SP-Sepharose HP and Superdex 75 resins.
• Each 50 ⁇ l enzymatic reaction contained 20 nM RNA template derived from the complementary sequence of the Internal Ribosome Entry Site (cIRES), 20 nM NS5B570n-Conl enzyme, 0.5 ⁇ Ci of tritiated UTP (Perkin Elmer catalog no. TRK-412; specific activity: 30 to 60 Ci/mmol; stock solution concentration from 7.5x10-5 M to 20.6x10-6 M), 1 ⁇ M each ATP, CTP, and GTP, 40 mM Tris-HCl pH 8.0, 40 mM NaCl, 4 mM DTT (dithiothreitol), 4 mM MgCl 2 , and 5 ⁇ l of compound serial diluted in DMSO.
• cIRES Internal Ribosome Entry Site
• Reaction mixtures were assembled in 96-well filter plates (cat # MADVNOB, Millipore Co.) and incubated for 2 h at 30° C. Reactions were stopped by addition of 10% final (v/v) trichloroacetic acid and incubated for 40 min at 4° C. Reactions were filtered, washed with 8 reaction volumes of 10% (v/v) trichloroacetic acetic acid, 4 reaction volumes of 70% (v/v) ethanol, air dried, and 25 ⁇ l of scintillant (Microscint 20, Perkin-Elmer) was added to each reaction well.
• scintillant Meroscint 20, Perkin-Elmer
• HCV Replicon assay This assay measures the ability of the compounds of formula I to inhibit HCV RNA replication, and therefore their potential utility for the treatment of HCV infections.
• the assay utilizes a reporter as a simple readout for intracellular HCV replicon RNA level.
• the Renilla luciferase gene was introduced into the first open reading frame of a genotype Ib replicon construct NK5.1 (N. Krieger et al, J. Virol. 2001 75(10):4614), immediately after the internal ribosome entry site (IRES) sequence, and fused with the neomycin phosphotransferase (NPTII) gene via a self-cleavage peptide 2A from foot and mouth disease virus (M. D. Ryan & J.
• RNA was electroporated into human hepatoma Huh7 cells, and G418 -resistant colonies were isolated and expanded.
• Stably selected cell line 2209-23 contains replicative HCV subgenomic RNA, and the activity of Renilla luciferase expressed by the replicon reflects its RNA level in the cells.
• the assay was carried out in duplicate plates, one in opaque white and one in transparent, in order to measure the anti- viral activity and cytotoxicity of a chemical compound in parallel ensuring the observed activity is not due to decreased cell proliferation or due to cell death.
• HCV replicon cells 2209-23
• Renilla luciferase reporter a Renilla luciferase reporter
• Dulbecco's MEM Invitrogen cat no. 10569-010
• FBS Invitrogen cat. no. 10082-1407
• dilutions of chemical compounds in the growth medium were added to the cells, which were then further incubated at 37 0 C for three days.
• the cells in white plates were harvested and luciferase activity was measured by using the R. luciferase Assay system (Promega cat no.
• WST-I reagent from Roche Diagnostic (cat no. 1644807) was used for the cytotoxicity assay. Ten microliter of WST-I reagent was added to each well of the transparent plates including wells that contain media alone as blanks. Cells were then incubated for 2 h at 37° C, and the OD value was measured using the MRX Revelation microtiter plate reader (Lab System) at 450 nm (reference filter at 650 nm). Again CC50, the concentration of the drug required for reducing cell proliferation by 50% in relation to the untreated cell control value, can be calculated from the plot of percentage reduction of the WST-I value vs. drug concentration as described above.
• Example 12 Pharmaceutical compositions of the subject compounds for administration via several routes were prepared as described in this Example.
• composition for Oral Administration (A)
• composition for Oral Administration (B)
• the ingredients are combined and granulated using a solvent such as methanol.
• the formulation is then dried and formed into tablets (containing about 20 mg of active compound) with an appropriate tablet machine.
• composition for Oral Administration (C)
• Veegum K (Vanderbilt Co.) 1.0 g
• the active ingredient is dissolved in a portion of the water for injection. A sufficient quantity of sodium chloride is then added with stirring to make the solution isotonic. The solution is made up to weight with the remainder of the water for injection, filtered through a 0.2 micron membrane filter and packaged under sterile conditions.

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• 2010
  • 2010-04-22 MX MX2011011112A patent/MX2011011112A/es not_active Application Discontinuation
  • 2010-04-22 AU AU2010240888A patent/AU2010240888A1/en not_active Abandoned
  • 2010-04-22 KR KR1020117028008A patent/KR20120011880A/ko not_active Application Discontinuation
  • 2010-04-22 JP JP2012506485A patent/JP2012524752A/ja not_active Ceased
  • 2010-04-22 BR BRPI1016167A patent/BRPI1016167A2/pt not_active Application Discontinuation
  • 2010-04-22 EP EP10715229A patent/EP2421831A1/en not_active Withdrawn
  • 2010-04-22 SG SG2011077682A patent/SG175774A1/en unknown
  • 2010-04-22 CN CN2010800237591A patent/CN102448936A/zh active Pending
  • 2010-04-22 CA CA2758838A patent/CA2758838A1/en not_active Abandoned
  • 2010-04-22 WO PCT/EP2010/055309 patent/WO2010122082A1/en active Application Filing
  • 2010-04-23 US US12/766,064 patent/US8158803B2/en not_active Expired - Fee Related
• 2011
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